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The orphan G-protein-coupled receptor 37 (GPR37) colocalizes with the dopamine (DA) transporter (DAT) in mouse nigrostriatal presynaptic membranes, and its genetic ablation in homozygous null-mutant (GPR37-KO) mice provokes the marked increase of plasma membrane expression of DAT, alteration of psychostimulant-induced locomotor activity, and reduction of catalepsy induced by DA-receptor antagonists. We report that extracts from GPR37-KO mice displayed biochemical alterations of the nigrostriatal signaling pathways mediated by D1 and D2 dopaminergic receptors. Null-mutant mice showed an increase of the basal phosphorylation level of the D2-regulated Akt kinase. The basal phosphorylation of the D1-activated ERK2 kinase was not altered, but acute treatments with amphetamine or cocaine failed to produce its specific increase, as detected in samples from wild-type littermates. Furthermore, the chronic administration of cocaine to GPR37-KO mice did not increase the expression of the ΔFosB transcription factor isoforms. Consistently, behavioral analysis showed that null-mutant animals did not respond to the incentive properties of amphetamine or cocaine, in conditioned place preference tests. Thus, the lack of GPR37 affects both ERK2- and Akt-mediated striatal signaling pathways, impairing the biochemical and behavioral responses typically induced by acute and chronic administration of psychostimulant drugs.

The laboratory mouse is the premier animal model for studying human disease and thousands of mutants have been identified or produced, most recently through gene-specific mutagenesis approaches. High throughput strategies by the International Knockout Mouse Consortium (IKMC) are producing mutants for all protein coding genes. Generating a knock-out line involves huge monetary and time costs so capture of both the data describing each mutant alongside archiving of the line for distribution to future researchers is critical. The European Mouse Mutant Archive (EMMA) is a leading international network infrastructure for archiving and worldwide provision of mouse mutant strains. It operates in collaboration with the other members of the Federation of International Mouse Resources (FIMRe), EMMA being the European component. Additionally EMMA is one of four repositories involved in the IKMC, and therefore the current figure of 1700 archived lines will rise markedly. The EMMA database gathers and curates extensive data on each line and presents it through a user-friendly website. A BioMart interface allows advanced searching including integrated querying with other resources e.g. Ensembl. Other resources are able to display EMMA data by accessing our Distributed Annotation System server. EMMA database access is publicly available at http://www.emmanet.org.

The orphan G-protein-coupled receptor 37 (GPR37) is a substrate of parkin, and its insoluble aggregates accumulate in brain tissue samples of Parkinson's disease patients, including Lewy bodies and neurites. Parkin activates the clearance of the unfolded receptor, while the overexpression of GPR37, in the absence of parkin, can lead to unfolded protein-induced cell death. We found that overexpression of the human GPR37 receptor in HEK293 cells and consequent activation of an endoplasmic reticulum (ER) stress response had effects comparable to starvation, in inducing the cellular autophagic pathway. Treatment with specific modulators provided further evidence for the autophagic clearance of the overexpressed GPR37 protein, in detergent-soluble and -insoluble fractions, as confirmed by the conversion of the microtubule-associated protein 1, light chain 3 (LC3)-I marker to its LC3-II isoform. Furthermore, Gpr37-null mutant mice displayed consistent alterations of ER stress and autophagic pathway markers in brain tissue samples. These findings show that GPR37 overexpression per se can induce cellular autophagy, which may prevent the selective degeneration of GPR37-expressing neurons, as reported for Parkinson's and related neurodegenerative diseases.

The orphan G protein-coupled receptor 37 (GPR37) is a substrate of parkin; its insoluble aggregates accumulate in brain samples of Parkinson's disease patients. We report here that GPR37 interacts with the dopamine transporter (DAT) and modulates DAT activity. GPR37 and DAT were found colocalized in mouse striatal presynaptic membranes and in transfected cells and their interaction was confirmed by coimmunoprecipitation assays. Gpr37-null mutant mice showed enhanced DAT-mediated dopamine uptake in striatal membrane samples, with a significant increase in the number of plasma membrane DAT molecules. The null mutant mice also exhibited a decrease in cocaine-induced locomotor activity and in catalepsy induced by dopamine receptor antagonists. These results reveal the specific role of GPR37, a putative peptidergic G protein-coupled receptor, in modulating the functional expression of DAT and the behavioral responses to dopaminergic drugs.

GPR37 is an orphan G protein-coupled receptor expressed in mammalian brain, and its insoluble aggregates are found in the brain samples of juvenile Parkinson's disease patients. We have produced a Gpr37 knock-out mouse strain and identified several phenotypic features that are similar to those reported for mutants of genes encoding components of synaptic dopamine vesicles. Our results reveal an unanticipated role of GPR37 in regulating substantia nigra-striatum dopaminergic signaling. Gpr37(-/-) mice are viable, with normal brain development and anatomy, but they exhibit reduced striatal dopamine content, enhanced amphetamine sensitivity, and specific deficits in motor behavior paradigms sensitive to nigrostriatal dysfunction. These functional alterations are not associated with any substantial loss of substantia nigra neurons or degeneration of striatal dopaminergic afferences, the main histological marks of Parkinson's disease. The inactivation of GPR37, in fact, has protective effects on substantia nigra neurons, causing resistance to treatment with the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

A case of perforated jejunal diverticulitis in a 87-year-old man is described and the literature is reviewed. Jejunal diverticulosis (JD) is estimated to occur in 0.02% to 1.3% of the adult population and is found most often in the elderly. The acute diverticulitis with perforation has been reported as high as 2.3% among patients with JD and is associated with high mortality. Clinical presentation mimic other more common acute intraperitoneal inflammatory conditions. Enteroclysis and abdominal CT are the most specific diagnostic tests. The common treatment is surgical resection of the involved segment. Laparoscopic resection and medical and medical/radiological approaches have also been proposed. Diagnostic and therapeutical aspects of this pathology are discussed.

We report the cloning of the mouse ortholog of the human GPR37 gene, which encodes an orphan G-protein-coupled receptor highly expressed in brain tissues and homologous to neuropeptide-specific receptors (D. Marazziti et al., 1997, Genomics 45: 68-77; Z. Zeng et al., 1997, Biochem. Biophys. Res. Commun. 233: 559-567). The genomic organization of the GPR37 gene is conserved in both mouse and human species with a single intron interrupting the receptor-coding sequence within the presumed third transmembrane domain. Comparative genetic mapping of the GPR37 gene showed that it maps to a conserved chromosomal segment on proximal mouse chromosome 6 and human chromosome 7q31. The mouse Gpr37 gene contains an open reading frame coding for a 600-amino-acid protein 83% identical to the human GPR37 gene product. The predicted mouse GPR37 protein contains seven putative hydrophobic transmembrane domains, as well as a long (249 amino acid residues), arginine- and proline-rich amino-terminal extracellular domain, which is also a distinctive feature of the human GPR37 receptor. Northern blot analysis of mouse tissues with Gpr37-specific probes revealed a main 3.8-kb mRNA and a much less abundant 8-kb mRNA, both expressed in the brain. A 3-kb mRNA is also expressed in the testis. Both the mouse and the human GPR37 genes may belong to a class of highly conserved mammalian genes encoding a novel type of G-protein-coupled receptor predominantly expressed in the brain., (Copyright 1998 Academic Press.)

Some second malignant neoplasms are increasingly being observed following NHL and a considerable amount of data has accumulated in the literature. The authors describe a case of 65-year old male who presented with submandibular adenopathy. Results of a biopsy of the mass surgically removed revealed low grade non-Hodgkin lymphoma. During the staging workup, a meningioma and a renal cell adenocarcinoma (RCC) were unexpectedly discovered and successively resected. The patient is currently alive with no evidence of metastatic diseases 12 months after diagnosis of non-Hodgkin's lymphoma (NHL), 10 months after meningioma resection and 8 months after RCC resection. The possibility of an underlying pathologic mechanism predisposing to multiple tumours should be considered. RCC and central nervous system (CNS) neoplasms are among second malignancies with higher incidences in non-Hodgkin lymphoma patients whereas with specific regard to meningioma, one of the most common benign intracranial tumours that sometimes shows biological aggressiveness and malignancy, we have currently no data in the literature. Increased risks for several malignancies occur late in the NHL follow-up period and are largely confined to patients receiving either radiation therapy or chemotherapy. On the other hand, increased risks for renal cancer have also been reported at less than one year after diagnosis of NHL and are present in all treatment subgroups (radiation therapy, chemotherapy, other-no treatment). Increased risks for CNS malignant neoplasms have also been reported at less than one year. The authors review the pathogenic significance of this case report neoplasms association in the light of the various explicative hypothesis of this concurrence. Possible immune mechanisms associated with these neoplasm are particularly pointed up.

A cDNA sequence encoding a putative peptide-specific G-protein-coupled receptor (GPR37) was isolated from a set of human brain frontal lobe expressed sequence tags. The GPR37 cDNA predicts a single open reading frame coding for a 613-amino-acid protein with seven hydrophobic transmembrane domains. The GPR37 genomic sequence was mapped to chromosome 7q31, and it was isolated upon screening of a chromosome 7-specific genomic library. The GPR37 gene spans more than 25 kb and contains two exons and a single intron which interrupts the GPR37 cDNA within the sequence encoding the presumed third transmembrane domain. Northern blot analysis with GPR37 probes revealed a main 3.8-kb mRNA and a less abundant 8-kb mRNA, both expressed in human brain tissues, particularly in corpus callosum, medulla, putamen, and caudate nucleus. The lowest level of expression was detected in cerebellum. The 3.8-kb mRNA is also less abundantly expressed in liver and placenta. Although the ligand for the putative GPR37 receptor has not been identified, its deduced amino acid sequence shows a high degree of homology (approximately 40% in the transmembrane regions) with most mammalian peptide-specific G-protein-coupled receptors and particularly with the human endothelin-B, bombesin-BB1, and bombesin-BB2 receptors.

A case of tumoral calcinosis of the hand is reported. The lesion was localized at the fifth digit of the right hand and caused pain and disability. The clinical, diagnostic and therapeutic problems of this rare soft tissue disease are discussed.

We have developed a replica filter assay that permits the direct identification of bacterial colonies expressing membrane receptors. E.coli transformed with appropriate phage or plasmid vectors containing human beta-adrenergic receptor cDNAs were grown on LB/agar plates. Bacterial colonies transferred onto nitrocellulose filters showed specific [125I]-iodocyanopindolol binding. beta-adrenergic receptors expressed in bacteria retained their pharmacological properties when transferred onto filters. This strategy, which is considerably simplified and more rapid compared to similar methods based upon expression of receptor genes in eukaryotic cells, may be a useful tool for cloning membrane receptors.

AtT20 (clone D16V) cells develop long neurite-like processes in the growth cones of which secretory granules containing ACTH accumulate. These secretory granules have an acidic pH. Using acridine orange as a vital stain for acidic organelles, in combination with video-enhanced fluorescence microscopy, and subsequent immunolabeling with rabbit antibodies against ACTH, we have shown that these secretory granules move by saltations along the processes. During saltations velocities of 3 to 5 microns/s are achieved. The majority of the secretory granules move in the anterograde direction but some move retrogradely. The growth cones and processes are the site of extensive endocytosis. Using Lucifer Yellow as a vital stain we have shown that most endosomes move by saltations retrogradely. Movement of both secretory granules and endosomes is dependent upon microtubules. Individual secretory granules or endosomes never reverse the direction of their movement as they traverse the processes. Neutralization of the lumen of these acidic organelles with NH4Cl does not inhibit their movement or change its direction.

In this work, the authors support the therapeutic validity of gastric-duodenal resection in urgency surgery. This study has been made on 479 cases observed during the last 21 years (1957-78). In 58 of them we have made a sinking of ulcer, in 421 patients we have made, immediatly, a gastric-duodenal resection with B II technique. On the base of the good obtained results, the authors conclude that the contro-indications to this operation (age, general conditions of patient, old pierce, etc.) that were accepted by the most surgeons up to few years ago, must considered of secondary importance.

The authors describe four cases of penetrating heart wounds: two from slash and puncture injuries and two from gunshot. Hearth lesions involved the left ventricle and pericardium in two cases, the right ventricle in one case, and only the diaphragmatic pericardium in one case. After a review of the literature, the authors discuss clinical and diagnostic problems relative to penetrating chest wounds and particularly those of the heart, stressing the need for very prompt diagnosis; as for actual treatment, they conclude that this can be carried out without any special problems in any Department of general emergency surgery.

The authors describe 9 cases of primitive tumors of the small gut (3 adenocarcinomas, 2 lymphosarcomas, 1 fibroma, 1 angioma, and 2 leiomyosarcomas, one being the cause of active hemorrhage). In all cases the tumors were diagnosed only at operation, which was invariably necessitated by complications. Seven patients underwent emergency surgery for intestinal obstruction; one underwent an exploratory laparotomy for recurrent intestinal bleeding caused by an angioma of the ileum; and the last of this series (exceptional enough to warrant separate reporting elsewhere) was operated upon as an emergency case when the tumor, precisely a leiomyosarcoma, was perforated and actively bleeding.